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Genetic basis for the origin of cardiac arrhythmias: Implications for therapy

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Abstract

The recognition of the role that genetic abnormalities play in the generation of cardiac arrhythmias and sudden cardiac death has evolved enormously over the past decade. One result is new insight into underlying physiologic and pathophysiologic mechanisms. New therapies based on this evolving insight are being developed. This review summarizes recent discoveries with a focus on the genetic basis of cardiac arrhythmias and their implications for new therapies.

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References and Recommended Reading

  1. State-Specific Mortality from Sudden Cardiac Death — United States, 1999.MMWR Morb Mortal Wkly Rep 2002, 51:123–126.

  2. Abbott GW, Sesti F, Splawski I, et al.: MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999, 97:175–187.

    Article  PubMed  CAS  Google Scholar 

  3. Barhanin J, Lesage F, Guillemare E, et al.: (V)LQT1 and 1sK(mink) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996, 384:78–80.

    Article  PubMed  CAS  Google Scholar 

  4. Chevalier P, Rodriguez C, Bontemps L, et al.: Noninvasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc Res 2001, 50:386–398.

    Article  PubMed  CAS  Google Scholar 

  5. January CT, Gong Q, Zhou Z: Long QT syndrome: Cellular basis and arrhythmia mechanism in LQT2. J Cardiovasc Electrophysiol 2000, 11:1413–1418.

    Article  PubMed  CAS  Google Scholar 

  6. Splawski I, Shen J, Timothy KW, et al.: Spectrum of mutations in long QT syndrome genes. Circulation 2000, 102:1178–1185. An excellent review of identified gene mutations in congenital long QT syndromes. This paper catalogues known mutations.

    PubMed  CAS  Google Scholar 

  7. Schwartz PJ, Priori SG, Dumaine R, et al.: A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000, 343:262–267. An original clinical report linking SIDS with genetic mutations associated with the long QT syndrome. It provides molecular evidence for this concept.

    Article  PubMed  CAS  Google Scholar 

  8. Wedekind H, Smits JP, Schulze-Bahr E, et al.: De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation 2001, 104:1158–1164.

    PubMed  CAS  Google Scholar 

  9. Ackerman MJ, Siu BL, Sturner WQ, et al.: Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001, 286:2264–2269. The largest published series of potential SIDS mutations performed as a molecular autopsy.

    Article  PubMed  CAS  Google Scholar 

  10. Schwartz PJ, Priori SG, Bloise R, et al.: Molecular diagnosis in a child with sudden infant death syndrome. Lancet 2001, 358:1342–1343.

    Article  PubMed  CAS  Google Scholar 

  11. Chen Q, Kirsch GE, Zhang D, et al.: Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998, 392:293–296.

    Article  PubMed  CAS  Google Scholar 

  12. Priori SG, Napolitano C, Gasparini M, et al.: Natural history of Brugada syndrome: Insights for risk stratification and management. Circulation 2002, 105:1342–1347.

    Article  PubMed  Google Scholar 

  13. Weiss JN, Barmada MM, Mguyen R, et al.: Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Circulation 2002, 105:707–713.

    Article  PubMed  CAS  Google Scholar 

  14. Akai J, Makita N, Sakurada H, et al.: A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome. FEBS Lett 2000, 479:29–34.

    Article  PubMed  CAS  Google Scholar 

  15. Schott JJ, Alshinawi C, Kyndt F, et al.: Cardiac conduction defects associate with mutations in SCN5A. Nat Genet 1999, 23:20–21.

    Article  PubMed  CAS  Google Scholar 

  16. Tan HL, Bink-Boelkens MT, Bezzina CR, et al.: A sodiumchannel mutation causes isolated cardiac conduction disease. Nature 2001, 409:1043–1047.

    Article  PubMed  CAS  Google Scholar 

  17. Wang DW, Viswanathan PC, Balser JR, et al.: Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation 2002, 105:341–346.

    Article  PubMed  CAS  Google Scholar 

  18. Haissaguerre M, Shah DC, Jais P, et al.: Role of Purkinje conducting system in triggering of idiopathic ventricular fibrillation. Lancet 2002, 359:677–678.

    Article  PubMed  Google Scholar 

  19. Marks AR, Priori S, Memmi M, et al.: Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. J Cellular Physiol 2002, 190:1–6.

    Article  CAS  Google Scholar 

  20. Smith TW: Digitalis Glycosides. Orlando: Grune & Stratons; 1986.

  21. Swan H, Piippo K, Viitasalo M, et al.: Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999, 34:2035–2042.

    Article  PubMed  CAS  Google Scholar 

  22. Laitinen PJ, Brown KM, Piippo K, et al.: Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 2001, 103:485–490.

    PubMed  CAS  Google Scholar 

  23. Priori SG, Napolitano C, Tiso N, et al.: Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001, 103:196–200.

    PubMed  CAS  Google Scholar 

  24. Kauffman ES, Priori SG, Napolitano C, et al.: Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: Experience in 101 related family members. J Cardiovasc Electrophysiol 2001, 12:455–461.

    Article  Google Scholar 

  25. Moss AJ: Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol 1993, 72:23B-25B.

    Article  PubMed  CAS  Google Scholar 

  26. Malfatto G, Beria G, Sala S, et al.: Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol 1994, 23:296–301.

    Article  PubMed  CAS  Google Scholar 

  27. Nador F, Beria G, De Ferrari GM, et al.: Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications. Circulation 1998, 32:486–491.

    Google Scholar 

  28. Swan H, Saarinen K, Kontula K, et al.: Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1. J Am Coll Cardiol 1998, 32:486–491.

    Article  PubMed  CAS  Google Scholar 

  29. Eggeling T, Osterhues HH, Hoeher M, et al.: Value of Holter monitoring in patients with the long QT syndrome. Cardiology 1992, 81:107–114.

    Article  PubMed  CAS  Google Scholar 

  30. Swan H, Viitasalo M, Piippo K, et al.: Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. J Am Coll Cardiol 1999, 34:823–829.

    Article  PubMed  CAS  Google Scholar 

  31. Members of the Sicilian Gambit: New approaches to antiarrhythmic therapy: emerging therapeutic applications of the cell biology of cardiac arrhythmias. Circulation 2001, Part 1, 104:2865–2873 and Part 2, 104:2990-2994. This is an extensive commentary by a committee of basic science and clinical electrophysiologists on the potential roles of genetics and cellular biology in arrhythmia management.

    Google Scholar 

  32. Roden DM and Spooner PM: Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis. J Cardiovasc Electrophysiol 1999, 10:1664–1683.

    Article  PubMed  CAS  Google Scholar 

  33. Nagatomo T, January CT, Makielski JC: Preferential block of late sodium current in the LQT3 delta KPQ mutant by the class 1C antiarrhythmic flecainide. Molec Pharmacol 2000, 57:101–107.

    CAS  Google Scholar 

  34. Zhou A, Gong Q, Epstein ML, January CT: HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem 1998, 273:21061–21066.

    Article  PubMed  CAS  Google Scholar 

  35. Furutani M, Trudeau MC, Hagiwara N, et al.: A novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation 1999, 99:2290–2294.

    PubMed  CAS  Google Scholar 

  36. Zhou Z, Gong Q, January CT: Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem 1999, 274:31123–31126.

    Article  PubMed  CAS  Google Scholar 

  37. January CT: Defective protein trafficking of HERG K+ channels in human congenital long QT syndrome. Pharmaceutical News 2000, 7:27–34.

    CAS  Google Scholar 

  38. Ficker E, Obejero-Paz CA, Zhao S, Brown AM: The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem 2002, 277:4989–4998.

    Article  PubMed  CAS  Google Scholar 

  39. Rajamani S, Anderson CL, Anson BD, January CT: Pharmacological rescue of human K+ channel LQT2 mutations: HERG rescue without block. Circulation 2002, 105:2830–2835. This is an important paper reporting a potential new approach to antiarrhythmic therapy for treating trafficking-defective LQT2 mutations.

    Article  PubMed  CAS  Google Scholar 

  40. Valdivia CR, Ackerman MJ, Tester DA, et al.: A novel SCN5A arrhythmia mutation M1766L with expression defect rescued by mexiletine. Cardiovasc Res 2002, in press.

  41. Nuss HB, Marban E, Johns DC: Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. J Clin Invest 1999, 103:889–896.

    Article  PubMed  CAS  Google Scholar 

  42. Donahue JK, Heldman AW, Fraser H, et al.: Focal modification of electrical conduction in the heart by viral gene transfer. Nat Med 2000, 6:1395–1398.

    Article  PubMed  CAS  Google Scholar 

  43. Wang Q, Curran ME, Splawski I, et al.: Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996, 12:17–23.

    Article  PubMed  Google Scholar 

  44. Curran ME, Splawski I, Timothy KW, et al.: A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995, 80:795–803.

    Article  PubMed  CAS  Google Scholar 

  45. Wang Q, Shen J, Splawski I, et al.: SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995, 80:805–811.

    Article  PubMed  CAS  Google Scholar 

  46. Schott JJ, Charpentier F, Peltier S, et al.: Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet 1995, 57:1114–1122.

    PubMed  CAS  Google Scholar 

  47. Splawski I, Tristani-Firouzi M, Lehmann MH, et al.: Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997, 17:338–340.

    Article  PubMed  CAS  Google Scholar 

  48. Tristani-Firouzi M, Bendahhou S, Tawil R, et al.: Functional characterization of mutations in Kir2.1 that cause long QT and periodic paralysis (Andersen’s syndrome) [abstract]. Biophys J 2002, 82:352a.

    Google Scholar 

  49. Neyroud N, Tesson F, Denjoy I, et al.: A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997, 15:186–189.

    Article  PubMed  CAS  Google Scholar 

  50. Schulze-Bahr E, Wang Q, Wedekind H, et al.: KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet 1997, 17:267–268.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Section of Cardiovascular Medicine, University of Wisconsin Hospitals and Clinics, Room H6/354 CSC (3248), 600 Highland Avenue, 53792, Madison, WI, USA

    Mackenzi Mbai MD, Sridharan Rajamani PhD, Brian P. Delisle PhD, Blake D. Anson PhD, Corey Anderson BS, Jonathan C. Makielski MD & Craig T. January MD, PhD

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  1. Mackenzi Mbai MD
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  2. Sridharan Rajamani PhD
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  3. Brian P. Delisle PhD
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  6. Jonathan C. Makielski MD
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  7. Craig T. January MD, PhD
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Mbai, M., Rajamani, S., Delisle, B.P. et al. Genetic basis for the origin of cardiac arrhythmias: Implications for therapy. Curr Cardiol Rep 4, 411–417 (2002). https://doi.org/10.1007/s11886-002-0041-5

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  • DOI: https://doi.org/10.1007/s11886-002-0041-5

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